Identification of p100 as a coactivator for STAT6 that bridges STAT6 with RNA polymerase II

Yang, Jie; Aittomäki, Saara; Pesu, Marko; Carter, Kara; Saarinen, Jyrki; Kalkkinen, Nisse; Kieff, Elliott; Silvennoinen, Olli

doi:10.1093/emboj/cdf463

Cited by 157 publications

(185 citation statements)

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“…MTDH has been localized most commonly to the endoplasmic reticulum/perinuclear region but has also been observed in the nucleus, nucleolus, and plasma membrane (19,20). SND1 has been localized to both the nucleus and the endoplasmic reticulum (22,23,(25)(26)(27). Using immunofluorescence analyses in LM2 cells, endogenous MTDH and SND1 were each observed to abundantly localize to the endoplasmic reticulum region with a more diffuse signal observed in the cytoplasm (Fig.…”

Section: Identification Of Snd1 As An Mtdh-interacting Protein-tomentioning

confidence: 93%

“…We identified and characterized the interaction between MTDH and one such protein, SND1. SND1 is a multifunctional protein with reported roles in transcriptional activation (22), RNA editing (23,24), formation of the RNAinduced silencing complex (25), and regulation of spliceosome activity (26) and the apoptotic cascade (27). However, its functional role in tumorigenesis or metastasis has not yet been evaluated.…”

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confidence: 99%

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Identification of Staphylococcal Nuclease Domain-containing 1 (SND1) as a Metadherin-interacting Protein with Metastasis-promoting Functions

Blanco

Alečković

Hua

et al. 2011

Journal of Biological Chemistry

114

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Metastasis is the deadliest and most poorly understood feature of malignant diseases. Recent work has shown that Metadherin (MTDH) is overexpressed in over 40% of breast cancer patients and promotes metastasis and chemoresistance in experimental models of breast cancer progression. Here we applied mass spectrometry-based screen to identify staphylococcal nuclease domain-containing 1 (SND1) as a candidate MTDH-interacting protein. After confirming the interaction between SND1 and MTDH, we tested the role of SND1 in breast cancer and found that it strongly promotes lung metastasis. SND1 was further shown to promote resistance to apoptosis and to regulate the expression of genes associated with metastasis and chemoresistance. Analyses of breast cancer clinical microarray data indicated that high expression of SND1 in primary tumors is strongly associated with reduced metastasis-free survival in multiple large scale data sets. Thus, we have uncovered SND1 as a novel MTDH-interacting protein and shown that it is a functionally and clinically significant mediator of metastasis.Metastasis is responsible for the majority of cancer-related deaths (1). An increasing number of genes have been implicated in mediating different steps of metastasis, but relatively few are mechanistically well characterized (2). One recently verified mediator of distant metastasis is Metadherin (MTDH 3 ; also called Lyric and AEG1 (3-5)). MTDH has been shown to be a key functional target of the 8q22 genomic gain that is frequently observed in poor prognosis breast cancer patients (6). Beyond promoting experimental lung metastasis (3, 6), multiple studies have implicated MTDH as a mediator of several cancer-related processes, such as oncogenesis and angiogenesis (7,8), invasion (9), chemoresistance (6, 10 -12), apoptosis resistance (13), and autophagy (14). Despite the abundance of MTDH phenotypes, a consensus understanding of its underlying molecular mechanisms has not yet been reached. MTDH has been shown to influence several oncogenic signaling pathways and transcription factors, such as Ha-Ras (15), PI3K/AKT (13), ERK, Wnt/␤-catenin (8), NF-B (16), c-Myc (15), and FOXO1/FOXO3a (17, 18). However, MTDH regulation of signaling pathways appears to be context-dependent with affected pathways varying by tumor type and cell line (19,20). Furthermore, prior work on MTDH molecular mechanisms has largely focused on hypothesis-driven investigations into the ability of MTDH to influence classical oncogenic pathways with little exploration to date on protein-level interactions (16,21).In this study, we aimed to expand the knowledge of MTDH molecular functionality and also uncover novel genes involved in promoting distant metastasis. Our approach utilized an unbiased, mass spectrometry-based screen for MTDH-interacting partners. We identified and characterized the interaction between MTDH and one such protein, SND1. SND1 is a multifunctional protein with reported roles in transcriptional activation (22), RNA editing (23, 24), formation of the RNAinduced ...

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Section: Identification Of Snd1 As An Mtdh-interacting Protein-tomentioning

confidence: 93%

mentioning

confidence: 99%

Identification of Staphylococcal Nuclease Domain-containing 1 (SND1) as a Metadherin-interacting Protein with Metastasis-promoting Functions

Blanco

Alečković

Hua

et al. 2011

Journal of Biological Chemistry

114

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“…COS-7 and Ramos cells were transfected by electroporation at 220 V/950 mF with a Bio-Rad gene pulser (14). The transfections of HeLa cells were performed using the calciumphosphate co-precipitation method (14).…”

Section: Methodsmentioning

confidence: 99%

PTB-associated Splicing Factor (PSF) Functions as a Repressor of STAT6-mediated Igϵ Gene Transcription by Recruitment of HDAC1

Dong

Zhang

et al. 2011

Journal of Biological Chemistry

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“…It interacts with several transcription factors and acts as a bridge between them and the transcriptional apparatus. 34,35 Furthermore, it interacts with the snRNPs and accelerates the kinetics of spliceosome assembly, thereby facilitating pre-mRNA splicing. 36,37 SND1 is also a component of the RNA-induced silencing complex that regulates RNAi-mediated gene silencing.…”

Section: Introductionmentioning

confidence: 99%

The transcriptional co-activator SND1 is a novel regulator of alternative splicing in prostate cancer cells

et al. 2013

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Splicing abnormalities have profound impact in human cancer. Several splicing factors, including SAM68, have pro-oncogenic functions, and their increased expression often correlates with human cancer development and progression. Herein, we have identified using mass spectrometry proteins that interact with endogenous SAM68 in prostate cancer (PCa) cells. Among other interesting proteins, we have characterized the interaction of SAM68 with SND1, a transcriptional co-activator that binds spliceosome components, thus coupling transcription and splicing. We found that both SAM68 and SND1 are upregulated in PCa cells with respect to benign prostate cells. Upregulation of SND1 exerts a synergic effect with SAM68 on exon v5 inclusion in the CD44 mRNA. The effect of SND1 on CD44 splicing required SAM68, as it was compromised after knockdown of this protein or mutation of the SAM68-binding sites in the CD44 pre-mRNA. More generally, we found that SND1 promotes the inclusion of CD44 variable exons by recruiting SAM68 and spliceosomal components on CD44 pre-mRNA. Inclusion of the variable exons in CD44 correlates with increased proliferation, motility and invasiveness of cancer cells. Strikingly, we found that knockdown of SND1, or SAM68, reduced proliferation and migration of PCa cells. Thus, our findings strongly suggest that SND1 is a novel regulator of alternative splicing that promotes PCa cell growth and survival.Oncogene advance online publication, 2 September 2013; doi:10.1038/onc.2013.360Keywords: alternative splicing; SND1; SAM68; CD44; prostate cancer INTRODUCTION Nuclear processing of pre-mRNAs requires tightly regulated steps that ultimately yield a mature and functional mRNA. Splicing is the step that insures the removal of long non-coding sequences (introns) from the pre-mRNA and the joining of the exons. This phenomenon is driven by a large macromolecular complex, the spliceosome, composed of five small nuclear ribonucleoproteins (snRNPs) and over 200 auxiliary proteins. 1 In higher eukaryotes, a large number of exons can be alternatively spliced to yield different transcripts from a single gene, thereby increasing the coding potential of the genome. 2,3 Indeed, the large majority of multi-exon human genes undergo alternative splicing (AS) to produce at least two mRNA variants. 4,5 As regulation of AS profoundly influences physiological and pathological processes, 3,6 the full comprehension of the molecular mechanisms regulating this step of pre-mRNA processing is of fundamental importance.Splicing is physically and functionally coupled to transcription. 7-10 Two models have been proposed for how transcription might affect changes in AS patterns. The 'recruitment model' suggests that the transcription apparatus physically interacts with splicing regulators, thereby affecting splicing decisions. The C-terminal domain (CTD) of the largest subunit of the RNA polymerase II (RNAPII) has a central role in this coupling process by favoring the recruitment of RNA processing factors on the nascent transcripts. 9,10 ...

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Identification of p100 as a coactivator for STAT6 that bridges STAT6 with RNA polymerase II

Cited by 157 publications

References 39 publications

Identification of Staphylococcal Nuclease Domain-containing 1 (SND1) as a Metadherin-interacting Protein with Metastasis-promoting Functions

Identification of Staphylococcal Nuclease Domain-containing 1 (SND1) as a Metadherin-interacting Protein with Metastasis-promoting Functions

PTB-associated Splicing Factor (PSF) Functions as a Repressor of STAT6-mediated Igϵ Gene Transcription by Recruitment of HDAC1

The transcriptional co-activator SND1 is a novel regulator of alternative splicing in prostate cancer cells

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